The present invention relates to emulsions for bioactive agent delivery and, more particularly, to emulsions prepared from phospholipids having high HLB values and preferably of low toxicity as well as homogenous and stable.
It has been proposed to deliver a bioactive agent (e.g. a drug, imaging agent or diagnostic agent), especially parenterally, to a patient by formulating such bioactive agent in an emulsion. Thus, typically, the bioactive agent is combined with an oil phase, a water phase and a surfactant. One problem with such delivery systems, however, has been the limited availability of surfactants which are considered biocompatible or non-toxic. It is well known that certain surfactants induce hemolysis while others have been shown to possess toxic effects relative to protein denaturation, capillary permeability, membrane bound enzyme activity and cellular histamine release.
In view of the above-described toxicity problems, naturally derived surfactants such as phospholipids have been proposed for formulating parenteral bioactive agent emulsions. For example, phosphatide stabilized emulsions of soy, safflower and cottonseed oil are currently accepted for administration to humans as intravenous nutrition supplements. Phosphatide emulsion systems have also been applied to the delivery of prostaglandin E1, corticosteroids, and indomethacin.
The bulk surfactant employed in the preparation of phospholipid emulsions is lecithin or phosphatidylcholine, it being understood that lecithin typically includes mixtures of various phosphatides. For example, commercial lecithin as supplied for intravenous fat emulsions is made up predominantly of phosphatidylcholine and phosphatidylethanolamine, with minor percentages of lysophosphatidylcholine, sphingomyelin, phosphatidic acid, phosphatidyl inositol, phosphatidylserine, and cholesterol.
While the phosphatide surfactants described above overcome the toxicity problems associated with the use of most conventional surfactants in parenteral emulsions, they have been somewhat limited in their application due to their narrow hydrophile-lipophile-balance (HLB) range. As is known by persons skilled in the art, the empirically determined HLB value of a surfactant designates the ability of such surfactant to emulsify oils having HLB requirements between about 1 and 20 but further including materials such as perfluorocarbons. Currently known emulsion systems based on phosphatide surfactants are based on the ability of the surfactants to emulsify oils having a relatively narrow HLB requirement of about 6. Thus, for example, phosphatidylcholine which is the primary ingredient in phosphatide mixtures has a required HLB value of only 7.6 when tested in its pure state. Therefore, oils such as corn oil, castor oil, mineral oil and palm oil having higher HLB requirements, e.g., above 8, could not be stabilized with conventional phosphatide surfactants.
Not surprisingly, therefore, emulsions for parenteral bioactive agent delivery have gained only a very limited acceptance. Thus, while a wide variety of commercial surfactants having HLB values ranging from 1-20 are available, precious few of those surfactants are suitable for parenteral administration to a patient. Additionally, the few surfactants suitable for parenteral administration can form stabilized emulsions with an oil only at a very narrow HLB range, which is far too low for emulsification of many oils.